There is a need for novel treatments for pain and inflammation. The current agents are inadequate and can, for example, cause unacceptable side effects. Additionally, the growing concern about the potential for addiction with opioid pain treatment further supports the need for new pain therapies. In particular, there is a need for new products for the treatment of ocular neuropathic pain (e.g. corneal neuropathic pain) and/or inflammation (e.g. uveitis).
Cannabinoids have been used for systemic treatment of pain and inflammation. All of the cannabinoids currently sold for human use also exhibit cannabinoid receptor type 1 (CB1) effects which are associated with, for example, hypothermia, catalepsy, hypolocomotion and psychoactive effects so these agents are associated with sedation and other effects that may limit, for example, systemic dosing.
Both CB1 and CB2 receptors have been reported to be upregulated following trauma and inflammation (Pertwee 2008; 2009; 2012; Guindon and Hohmann, 2008). Activation of downstream pathways associated with these receptors is analgesic, anti-inflammatory and, in the case of CB1, can promote cellular proliferation and wound healing (Yang, 2013).
CBD-DMH, like its parent molecule, cannabidiol (CBD), is non-psychotropic and exhibits analgesic and anti-inflammatory effects in animal models. However, CBD-DMH is reported to be more than 10-fold more potent than CBD. The structure of CBD and CBD-DMH have been previously described (Mechoulam et al., 2002; Fride et al., 2004).
HU-308 is a synthetic cannabinoid compound that binds and activates the CB2 receptor specifically (Hanus 1999). An enantiomeric derivative of HU-308, named HU-433, is also a CB2 agonist. HU-433 has been shown to have 2-3 orders of magnitude greater potency in both in vitro and in vivo systems. It shows no psychoactivity. The chemical structures of HU-308 and HU-433 were previously described in PCT Publication No. WO 2010/041253.
Without being bound by theory, cannabis synergy arises from constituent combination effects (Berenbaum 1989; McPartland and Russo 2001; Russo 2011). This may occur via several mechanisms including but not limited to: multi-target effects (receptor agonism or antagonism, anti-oxidant, modulation of endogenous endocannabinoid synthesis or metabolism, etc.), improved pharmacokinetic properties of compounds via modulation of solubility, bioavailability, as well as potential bacteriostatic activity (Wagner and Ulrich-Merzenich 2009; Russo 2011). CBD synergy with other phytocannabinoids and terpenoids from Cannabis has been reported specifically with regard to the treatment of inflammation and pain (Russo, 2011).
Inflammatory eye diseases represent a particular challenge due, for example, to risk of vision loss and blindness. The conditions encompass intraocular inflammation (e.g. uveitis, uveoretinitis, proliferative vitreoretinopathy) as well as extraocular inflammation, including corneal inflammation and neuropathology.
Collectively, ocular inflammation contributes significantly to the global incidence of blinding eye disease and can be a debilitating condition with a high medical and economic burden on populations.
Neuropathic Pain
Neuropathic pain is generated by pathology in the peripheral or central nervous system. A large number of disorders can give rise to neuropathic pain. This may range from nerves being cut (trauma or surgery) or damaged by viruses, ischemic and metabolic injury or complex genetic disorders to name a few. Neuropathic pain may arise from local damage to neural tissues as well as tissues remote to initial trauma and may also arise as a result of chronic inflammatory disease. Pharmacological management is one of the most used pain treatment options but results are poor with many patients obtaining inadequate relief with currently available agents. There is therefore a need for new agents for treatment of neuropathic pain. Neuropathic pain may affect any part of the body including the eye for which there are no adequate treatments at present.
Intraocular Inflammation and Optional Pain
Uveitis is a term used to describe any intraocular inflammation within the eye from the uvea (iris, ciliary body and choroid) to the sclera, retina and optic nerve. It involves either infectious or non-infectious conditions, which can be localized within the eye or associated with systemic inflammatory and autoimmune diseases, including reactive arthritis and multiple sclerosis. The most common form of uveitis, anterior uveitis, with inflammation of the iris and ciliary body, is additionally associated with considerable pain and photophobia (Jabs, Nussenblatt et al. 2005; Lee and Dick 2012). Untreated uveitis can lead to permanent loss of vision. Severe uveitis is treated aggressively to mitigate the damage caused by inflammation. However, currently utilized agents, including the “gold-standard” corticosteroids, anti-metabolites, biologic response modifiers and non-steroidal anti-inflammatory agents, suffer from significant side-effects and in some cases escalating costs (i.e. biologics). A search for newer efficacious, safe and/or cost-effective anti-inflammatory and immunomodulatory agents, suitable for acute and chronic use, either as sole treatments or in combination, and delivered locally to the eye, is a priority for the future treatment of ocular inflammation in order to prevent loss of vision.
Anterior uveitis (iritis) is associated with inflammation of iris and anterior tissues and this leads to pain and light sensitivity with pupillary changes in response to light. Anterior uveitis pain is typically resolved when the inflammation is treated so is not classed as neuropathic pain. Generally uveitis represents hyperactivation of the body's immune system; a form of local sepsis. Inflammatory conditions are represented by activation, recruitment, and migration of immune cells, release of proinflammatory cytokines, swelling, oedema and/or tissue damage. In posterior uveitis, this can also include gliosis, and activation of resident immune cells (microglia). In some retinal inflammatory diseases, cell proliferation with subsequent fibrosis and retinal detachment is present (i.e. proliferative vitreoretinopathy).
Posterior uveitis is not clinically associated with pain. Generally conditions with moderate or mild chronic inflammation in the retina do not present with pain but can result in loss of retinal neurons and vision loss. These include: posterior uveitis, retinitis and proliferative vitreoretinopathy.
Extraocular Inflammation and Pain
Corneal neuropathic hyperalgesia involves a dysfunctional corneal pain system and is associated with significant discomfort and persistent heightened sensitivity of the cornea (peripheral sensitization) in the absence of overt trauma or noxious stimuli (reviewed in Belmonte et al., 2004; Rosenthal & Borsook, 2012; Rosenthal et al., 2009). Ongoing excitation of corneal nerves, following corneal damage or irritation, results in the release of neuropeptides and inflammatory mediators that augment the inflammatory reaction (neurogenic inflammation) leading to hyperalgesia. Corneal hypersensitivity, neuroinflammation, pain and photophobia are reported in patients following refractive surgery and chemical/toxic exposure, including repetitive use of benzalkonium chloride-preserved eye drops. Corneal neuropathic pain is also a central pathogenic feature of eye disorders that are collectively referred to as dry eye, and include non-infectious immunological causes such as Sjogren syndrome and systemic lupus as well as infections with Herpes Zoster (reviewed in Rosenthal & Borsook, 2012; Yawn et al., 2013). Up to 20% of adults aged 45 or older are affected by dry eye disease presenting a major health concern with significant economic and societal implications (reviewed in Friedman, 2013; Pflugfelder, 2008). In many cases dry eye disease is refractory to treatment and lacking in a clear association between symptoms and signs. For example, while inflammatory corneal hyperalgesia, as a result of ocular surface desiccation (evaporation dry eye), is the most common form of corneal hyperalgesia, many patients who report dry eye symptoms do not show signs of dry eyes (reduced tears), or superficial corneal erosions. Contrasted are others who have insufficient tear quantity and quality who are asymptomatic. Furthermore, neuropathic disease can sometimes precede alterations in tear film dynamics (Rosenthal & Borsook, 2012; Rosenthal et al., 2009).
Current agents prescribed for corneal neuropathic pain include a wide variety of distinct compounds such as but not limited to, opioids, non-steroidal anti-inflammatory drugs, sodium channel blockers (local anesthetics), anti-convulsants, tricyclic anti-depressants and GABAergic agents. However, present pharmacotherapy remains inadequate and the complex nature of corneal neuropathic pain is highlighted by the fact that no single known treatment appears to be effective in managing symptoms. Furthermore, the undesirable side-effects of many currently prescribed agents limit the therapeutic window for treatment. Corneal inflammatory neuropathic pain therefore represents a significant unmet therapeutic need (Rosenthal & Borsook, 2012; Rosenthal et al., 2009).
CBD, or CBD in combination with other endocannabinoid system modulators, has proven clinical and pre-clinical efficacy in the treatment of neuropathic pain resulting from nerve injury and disease (Hsieh et al., 2011; Ward et al., 2011; reviewed in Rahn and Hohmann 2009; Hohman & Suplita, 2006).